Antisense oligonucleotides have been developed over the past decade as selective chemotherapeutic agents with a novel mechanism of action, involving inactivation of specific gene sequences via complementary binding. Instability and other unfavorable chemical properties of early oligonucleotides have been circumvented by side chain modification of the native oligomer using sulfate and phosphate esters. GEM 91 is a 25- mer phosphorothioate antisense oligonucleotide complementary to the highly conserved RNA initiation sequence of the human immunodeficiency virus (HIV) gag protein (Agrawal and Tang, 1992). In vitro, GEM 91 is a potent and highly selective anti-HIV compound, with an IC50 against laboratory strains of 0. 04 uM , and an average IC50 against clinical isolates of 0. I uM. The anti-HIV activity of GEM 91 appears to be sequence-specific, since similar oligomers with random sequences are less potent against HIV by a factor of 100 or more. A limited number of options are currently available for treatment or prevention of HIV infection. GEM 91 is the first antisense oligonucleotide to be clinically tested against HIV. One potential advantage of this compound is that it targets a highly conserved and essential genetic element in HIV, making the emergence of drug resistant virus unlikely. Indeed, long-term in vitro studies have failed to select HIV isolates with reduced sensitivity to GEM 91. This suggests the possibility of long-lived therapeutic responses.